﻿A life with fever every ten days

— Marten Dooper, De Limburger, 1999

It’s not unusual for a bride to be in tears on the day of her wedding. But for Henriëtte Olland (28) there was a special reason to cry. “I was so happy that my one wish had come true. That day I did not have a fever. I was able to enjoy the party.”

The fact that Henriëtte had a normal temperature on that day may seem trivial, but it was special for her. She suffers from what physicians call the hyper-IgD syndrome. This is a rare disorder; about 150 patients have been identified so far worldwide. It is characterized by periodic fever attacks.

Henriëtte: “On average I’m about 10 days free of fever, and then I get a fever attack which lasts some 5 days. But it is impossible to predict an attack. So you can’t plan anything.” Like that time when she had managed to get her hands on tickets for a Stones concert. “On the day of the concert I got a fever attack. Instead of dancing, I was in my bed, crippled by pain and by a fever of 40 degrees celsius.” Those constant disappointments make the disorder mentally exhausting too. Henriëtte: “Everytime I only get a quick taste of the good life, before it ends in fever again.”

The disease is named for the abnormally high levels of IgD, a protein which is part of the immune system, in the blood of many patiënts who have these fever attacks, that disappear spontaneously every time, explains dr. Joost Drenth, working as internist-in-training in the academical hospital St. Radboud in Nijmegen, the Netherlands [translator’s note: Joost Drenth graduated as internist in january 2000, ﻿﻿is now Professor in Gastroenterology and in 2010 became head of the Department of Gastroenterology of the Radboud University Nijmegen Medical Centre]. “In addition, many patients suffer from painful, swolen joints, swollen lymphnodes and sometimes a skin rash”, says Drenth, who is considered to be the expert on this syndrome.

The hyper IgD syndrome is a congenital disease, and in many patients the fever attacks start from a few weeks after birth. In others, like Henriëtte, the disease only fully manifests itself at a later age. “As a child I would often have the flu or a cold, but the really serious fever attacks only started when I was about 17 years old. Once a month it was bingo: a high fever and not being able to walk because of the pain in my joints.”

Like all hyper IgD patients, Henriette was then caught up in the medical circus. Her general practitioner sent her to a specialist in internal medicine, and after that to another specialist in internal medicine etcetera. Nobody was able to find out what was the matter with her. Until a recommendation finally brought her to Drenth in Nijmegen. After four years of one hospital after another – Henriëtte: “And in every hospital they start all their tests from the beginning again” – finally the diagnosis was made: hyper IgD syndrome.

Henriëtte: “I had always told myself that once they knew what was the matter with me, the problem would be solved.” In that she was disappointed. Drenth: “There is still no cure for the disease. We don’t even know what causes it. And the link with the high levels of IgD is still a mystery.”

But the scientific knowledge about the disorder is growing every day. This month Drenth published an article in the renowned journal Nature Genetics, in which he describes the gene responsible for the disease. However, this does not mean that the suffering will be over soon.

Drenth: “To our great surprise, the defect is located in an enzyme which is involved in the synthesis of cholesterol in our body. It is still a mystery to us how this defect is linked to the fever attacks or the other symptoms. However, in the biochemical pathway to cholesterol there are a lot of side tracks which we now want to explore further. Possibly we will find something which can be corrected by medication. This discovery does make it easier to make the diagnosis of the disease. A simple bloodtest is all that is needed. That can save patients a lot of unnecessary treatments.”

After more than ten years of fever attacks Henriëtte has learned to live with the disorder, as good as is possible. “You can forget about a job. I did manage to pass my secondary school exams, but I had to quit the theater academy in Amsterdam after a few years. All projects I was involved in were delayed because I was ill every time.” A freelance job as theater critic at a newpaper was not feasible, either. “I couldn’t guarantee up front whether I would be able to work at a certain time.” The frustrating thing is that on her “good days”, as Henriëtte puts it, she has 150 procent energy.

That varying pattern also makes it difficult for outsiders to understand her disorder, she has found. “Many people only see me on my good days, so they know me as a healthy person. It is difficult for them to imagine that a day later I might be so ill that I can’t even take care of myself.” From self-protection, she has little dreams of the future. “I will just be glad if they find something to lessen the number of attacks.”

Discovery of a “fever gene” raises new questions

— Joke Groeneveld, Radbode, 1999

In 1984 the internist Prof. dr. Jos van der Meer was the first to describe the so-called hyper-IgD syndrome. Patients suffer from severe periodic attacks of fever without a clear cause, which start early in childhood. A high concentration of the protein immunoglobulin D (IgD) in their blood is characteristic; this is the reason for the name of the disorder. In the last few years, internist-in-training dr. Joost Drenth [translator’s note: Joost Drenth graduated as internist in january 2000, is now Professor in Gastroenterology and in 2010 became head of the Department of Gastroenterology of the Radboud University Nijmegen Medical Centre] has been examining this mysterious syndrome. Recently, he discovered a number of mutations in a gene on chromosome 12, which cause the hyper-IgD syndrome. This has led to a publication in the prestigious journal Nature Genetics this month [1999].

Drenth has examined some 120 patients with the hyper-IgD syndrome: about half of them is Dutch of origin. The other half has been referred to Nijmegen, the Netherlands, by members of an international Study Group, which consists of pediatricians and internists with a special interest in the syndrome.

The main symptom in all patients is the spiking fever, which occurs every four to eight weeks, and lasts three to seven days. The fever attacks usually start in the first months of life, and torment the patient a whole lifetime, although frequency and intensity can diminish at a later age. Apart from this, during fever attacks most patients have painful joints and swollen lymph nodes and they suffer from symptoms like stomachache, diarrhoea, vomiting and headaches.

Last year, Drenth stayed a few months in Généthon, a center for research of genetic disorders in Paris, to study the genetic material of the patients more closely. This was made possible by the Niels Stensen foundation, a fund which supports promising research by young scientists. “The Généthon has very advanced techniques at its disposal to test genetic markers”, according to Drenth. “That is the reason why I had localised the gene for the hyper-IgD syndrome within 2 months.” The step towards the final unraveling of the gene structure was comparatively easy after that.

It appeared that the gene encodes for the enzyme mevalonate kinase, which is one step in the conversion of mevalonic acid into cholesterol. From the literature it was known that patients with a severe illness, in which the body produces hardly any mevalonate kinase, suffer from fever attacks too. This provides the link with hyper-IgD. And it was shown by the group of Drenth that this enzyme doesn’t function properly in HIDS. The function is reduced to an average of seven procent of normal.

The discovery of the genetic defect which causes hyper-IgD, raises a lot of new questions. “The functional link between mevalonate kinase and the hyper-IgD syndrome is still absolutely unclear,” says Drenth. “The concentration of cholesterol of the patients is hardly different from the average population. This is also the case for the concentration of mevalonic acid. It’s still impossible to directly link mevalonate kinase and the raised concentration of immunoglobulin D in the patients, too.”

This discovery does prove that there are at least three different periodic fever syndromes. Apart from the hyper-IgD syndrome, these are the familiar Hibernian fever, which, as the name implies, was first described in an Irish family, and the familial Mediterranean fever, with a few thousands of patients in Israel and surrounding countries. These disorders are caused by a different genetic defect.

The publication in Nature Genetics provides the department of General Internal Medicine [of the University Medical Center St. Radboud of Nijmegen, the Netherlands] with an extra impulse to continue the research into hyper-IgD. Among other things, following studies will focus on the role of fever-inducing cytokines and the effect of drugs, including drugs which lower cholesterol concentration, for this disease.